TANGO2: a protein trafficking disease between organelles

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The TANGO family of proteins plays a crucial role in the interaction of the Golgi apparatus and the endoplasmic reticulum. The TANGO2 protein (Transport And Golgi Organization protein 2), encoded by the TANGO2 gene, is part of this family of transport or trafficking proteins between both organelles.

TANGO2 was first described in the Drosophila fly and later, Kremer et al (2016) observed that TANGO2 mutations caused a pediatric disease with multi-organ involvement.

TANGO2: a protein trafficking disease between organelles

What is the endoplasmic reticulum?

The endoplasmic reticulum is an organelle found in the cytoplasm of the cell and whose primary function is the synthesis of proteins and lipids (such as cholesterol, bile acids, etc…).

Many proteins must be modified with sugar chains (glycans) to modulate their function, and this glycosylation begins in the endoplasmic reticulum and ends in the Golgi.

What is the Golgi apparatus?

The Golgi apparatus is an organelle present in all cells, whose main mission is the modification, distribution and delivery of a large number of macromolecules (proteins and lipids), synthesized in the endoplasmic reticulum of the cell. A very complex and selective protein and lipid traffic takes place between both organelles, in which the TANGO proteins are involved, among many other specific proteins.

The proper functioning of all of them depends on the newly formed proteins efficiently reaching their final destinations, where they perform their specific functions.

What happens when mutations occur in the TANGO2 gene?

Mutations in the TANGO2 gene cause a defect in said intra-organelle trafficking protein, and are associated with a complex pediatric phenotype, with recurrent metabolic crises.

What clinical manifestations do patients with TANGO2 mutations present?

Patients present a clinical phenotype of progressive neurodevelopmental impairment and recurrent metabolic seizures, with rhabdomyolysis (muscle necrosis with release of muscle fiber contents into the blood), encephalopathy, seizures, lactic acidosis, hypoglycemia, hyperammonemia (in seizures). and cardiac arrhythmias.

Many patients have hypothyroidism. The episodes are often triggered by febrile infections, which cause irreversible brain damage and neurological impairment.

Other triggering factors are: fasting due to disease-related gastroenteritis and/or anorexia, fever, viral infections such as chickenpox, general anesthesia, or possibly the administration of L-carnitine, given the presentation resembling a mitochondrial beta-oxidation defect that require this therapy.

The prognosis is poor, with significant disability and early death in many of the affected individuals. Until now, there are no specific therapeutic options available, only symptomatic treatments.

Various series of patients have been described since 2016 and it is believed that this disease is underdiagnosed.

How is the diagnosis reached?

Through clinical suspicion (association of metabolic crises with rhabdomyolysis and/or neurodevelopmental delay and/or hypothyroidism) that leads to the genetic study of complete genome sequencing.

Why does the TANGO2 protein defect cause this complex phenotype?
This clinical picture resembles a combination of a very long-chain fatty acid beta-oxidation defect and a mitochondrial disease, falling into neither category.

For this reason, it is essential to discover exactly what the function of the TANGO2 protein is, as well as its location, in order to understand its role in the metabolic crises to which it is associated, in order to prevent them.

What studies were performed to discover the function and localization of the TANGO2 protein?

Since TANGO2 had been described to function in intra-organelle trafficking, but mutations in the gene give rise to clinical features similar to a mitochondrial energetic defect, it was important to clarify in which cell organelle the protein actually functions.

Studies performed on TANGO2 from flies and mice, as well as on fibroblasts from patients with mutations in this gene, revealed subtle or no effects on Golgi apparatus morphology or membrane trafficking. It was suggested that the protein played a role in mitochondrial physiology, but it was not clear in what way the protein was affecting this organelle.

Berat et al (2020) conclude that TANGO2 disease is unlikely to be caused by a primary mitochondrial defect, suggesting that the mitochondrial defects found in patients could be secondary to metabolic crises.

After multiple studies, Mingiruli et al (2020) suggest that mitochondrial function and endoplasmic reticulum-Golgi trafficking, along with proper processing of secreted proteins and fatty acid oxidation, are predominantly affected by the loss. the function of TANGO2.

Milev et al (2020) perform a membrane trafficking assay in fibroblasts from patients with TANGO2 mutations and show that there is a significant delay in the movement of proteins between the endoplasmic reticulum and the Golgi apparatus, which is attributed to a defect in the function of TANGO2.

In addition, they show that a portion of the TANGO2 protein is located in the mitochondria. Using fibroblasts from patients shows changes in mitochondrial morphology.

They conclude that TANGO2 functions both in membrane trafficking and in an as yet undetermined role in the physiology of mitochondria. The phenotype of affected individuals can be partially explained by this double involvement of the protein.

General considerations

  1. The genetic origin of a disease with a complex phenotype, observed in multiple patients, is investigated.
  2. This phenotype is found to be associated with the TANGO2 gene, previously described in the Drosophila fly. 
  3. TANGO2 is part of a family of membrane-trafficking proteins, involved in the complex interaction of the Golgi apparatus and the endoplasmic reticulum.
  4. It is essential to discover the location and function of TANGO2, in order to understand its relationship with the phenotype of patients and design a possible treatment that prevents their metabolic crises.
  5. Studies should continue to understand why TANGO2 deficiency causes such a complex phenotype. The large number of researchers from different countries who sign the articles on TANGO2 shows the need for coordination between them to describe long series of patients with rare diseases and to delve into their pathophysiology. 

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